The international DIRECT-SAFE trial has produced results indicating that intravenous thrombolysis (IVT) plus mechanical thrombectomy—commonly referred to as bridging therapy—should continue to be recommended as the standard treatment approach in large vessel occlusion (LVO) acute ischaemic stroke patients who present within 4.5 hours of symptom onset.
The trial’s findings, which ultimately did not show non-inferiority with direct mechanical thrombectomy compared to bridging therapy, have been published in The Lancet by Peter Mitchell (University of Melbourne, Melbourne, Australia) and colleagues, who note that “additional information from our study should inform guidelines to recommend bridging therapy as standard treatment”.
“The benefit of combined treatment with IVT before endovascular thrombectomy in patients with acute ischaemic stroke caused by LVO remains unclear,” they write at the outset of their publication. “We hypothesised that the clinical outcomes of patients with [LVO stroke] treated with direct endovascular thrombectomy within 4.5 hours would be non-inferior compared with the outcomes of those treated with standard bridging therapy (IVT before endovascular thrombectomy).”
This hypothesis was investigated via the DIRECT-SAFE study—an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial in which adult patients who presented within this early, 4.5-hour time window from stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam.
Eligible patients—those with stroke and an LVO in their intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast computed tomography (CT) and vascular imaging, were randomly assigned via a web-based, computer-generated randomisation procedure to either direct endovascular thrombectomy or bridging therapy on a 1:1 basis. Patients assigned to bridging therapy received alteplase- or tenecteplase-based IVT as per standard care at each site; and thrombectomy was also per standard of care, using the Trevo device (Stryker) as a first-line intervention.
The primary efficacy endpoint for DIRECT-SAFE was functional independence (modified Rankin Scale [mRS] score 0–2) or return to baseline at 90 days, with a non-inferiority margin of –0.1, analysed by intention to treat and per protocol. The intention-to-treat population was included in the safety analyses, Mitchell and colleagues note.
Between 2 June 2018, and 8 July 2021, 295 patients were randomly assigned to direct thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 55% of 146 patients in the direct thrombectomy group (n=80) and 61% of 147 patients in the bridging therapy group (n=89).
The researchers further detail that safety outcomes were similar between the two groups, with symptomatic intracerebral haemorrhage occurring in 1% of patients in the direct group (n=2) and 1% of 147 patients in the bridging group (n=1). In addition, 15% of patients in the direct group died (n=22) compared to 16% in the bridging group (n=24).
Speaking to NeuroNews following publication of this paper, Mitchell highlighted an additional take-home message from the study beyond the fact that eligible LVO stroke patients should receive IVT with alteplase or tenecteplase.
“A further, surprising finding of our study—that we cannot exclude being due to chance—is the differential response observed in Asian region versus non-Asian region patients,” he noted. “For reasons covered in the paper, we had hypothesised that the benefit of direct therapy may be larger in Asian region patients. [However], we observed an even lower proportion of patients in Asian regions treated with direct therapy achieving the primary outcome compared to the bridging therapy group.
“On the basis of the DIRECT-SAFE trial, patients with LVO ischaemic stroke eligible to receive thrombolytic therapy and mechanical thrombectomy should continue to receive bridging therapy. The DIRECT-SAFE investigators, together with the investigators of the other randomised trials into direct endovascular thrombectomy, have joined together to further investigate subgroups and outcomes with individual, patient-level meta-analysis—the IRIS collaboration.
“The ongoing research of the IRIS collaboration with increased numbers and statistical power may allow more insight into which patient subgroups show non-inferiority, and at what non-inferiority margin, [with] direct treatment, potentially allowing more individualised treatment decisions. For example, patients with large core infarcts presenting at later time intervals—yet still within guidelines for receiving intravenous thrombolytic therapy—with likely need for stent placement and antiplatelet medication, may be more safely treated with direct thrombectomy.”